Targeting of the CD161 Inhibitory Receptor Enhances T cell-mediated Immunity Against Hematological Malignancies
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ABSTRACT:
PROVIDER: PRJNA909225 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22548574_1.fastq.gz | Fastqsanger.gz | |||
| SRR22548574_2.fastq.gz | Fastqsanger.gz | |||
| SRR22548575_1.fastq.gz | Fastqsanger.gz | |||
| SRR22548575_2.fastq.gz | Fastqsanger.gz | |||
| SRR22548576_1.fastq.gz | Fastqsanger.gz |
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Project description:The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T cells in a number of human solid tumor types, and its ligand CLEC2D is expressed by both tumor cells and infiltrating myeloid cells. Here we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Line Encyclopedia (CCLE) revealed that CLEC2D mRNA was most abundant in hematological malignancies, including B cell and T cell lymphomas as well as lymphocytic and myelogenous leukemias. CLEC2D protein was detected by flow cytometry on a panel of cell lines representing a diverse set of hematological malignancies. We therefore used yeast display to generate a panel of high-affinity, fully human CD161 monoclonal antibodies (mAbs) that blocked CLEC2D binding. These mAbs were specific for CD161 and had a similar affinity for human and non-human primate CD161, a property relevant for clinical translation. A high-affinity CD161 mAb enhanced key aspects of T cell function, including cytotoxicity, cytokine production and proliferation, against cell lines originating from patients with AML, DLBCL and Burkitt lymphoma. In humanized mouse models, this CD161 mAb enhanced T cell-mediated immunity resulting in a significant survival benefit. ScRNA-seq data demonstrated that CD161 mAb treatment enhanced expression of cytotoxicity genes by CD4 T cells as well as a tissue-resident memory program by CD4 and CD8 T cells that is associated with favorable survival outcomes in multiple human cancer types. These fully human monoclonal antibodies thus represent potential immunotherapy agents for hematological malignancies.
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Project description:T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA-seq to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with IDH-wildtype glioblastoma and IDH-mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several NK cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.
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Project description:Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T-cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. In this study, we performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlation between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. Microarray gene expression analysis was performed on hematological malignancies of different origins and their healthy hematopoietic counterparts as well as on healthy non-hematopoietic cell types from organs that are often targeted in Graft-versus-Host Disease (166 samples in total). Various non-hematopoietic cell types were cultured in the presence of IFN-γ or T-cell culture supernatant to allow gene expression analysis under inflammatory conditions. Malignant and healthy hematopoietic cells were isolated by flow cytometry based on expression of specific surface markers and healthy non-hematopoietic cell types were isolated or cultured from tissue biopsies or surgically removed specimen. Various non-hematopoietic cell types were in vitro cultured for 4 days in the presence of IFN-γ or T-cell culture supernatant to mimic inflammation. The dataset allows comparison of gene expression between hematological malignancies and healthy non-hematopoietic cell types to estimate efficacy and toxicity of immunotherapeutic targets for hematological malignancies. Total RNA was isolated from (malignant) hematopoietic cells isolated by flow cytometry based on expression of specific surface markers and from healthy non-hematopoietic cell types isolated or cultured from tissue biopsies or surgically removed specimen. From various non-hematopoietic cell types, total RNA was also isolated after 4 days of in vitro culture in the presence of IFN-γ or T-cell culture supernatant.
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Project description:Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T-cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. In this study, we performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlation between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. Microarray gene expression analysis was performed on hematological malignancies of different origins and their healthy hematopoietic counterparts as well as on healthy non-hematopoietic cell types from organs that are often targeted in Graft-versus-Host Disease (166 samples in total). Various non-hematopoietic cell types were cultured in the presence of IFN-γ or T-cell culture supernatant to allow gene expression analysis under inflammatory conditions. Malignant and healthy hematopoietic cells were isolated by flow cytometry based on expression of specific surface markers and healthy non-hematopoietic cell types were isolated or cultured from tissue biopsies or surgically removed specimen. Various non-hematopoietic cell types were in vitro cultured for 4 days in the presence of IFN-γ or T-cell culture supernatant to mimic inflammation. The dataset allows comparison of gene expression between hematological malignancies and healthy non-hematopoietic cell types to estimate efficacy and toxicity of immunotherapeutic targets for hematological malignancies.
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